EASL 2013: 利兹HighleymanTruvada:乙型肝炎患者免疫耐受效果最好

StephenW

EASL 2013: Truvada Works Best for Immune-Tolerant Hepatitis B Patients -- But Do They Need Treatment?

   
    Published on Monday, 29 April 2013 00:00
    Written by Liz Highleyman


A combination of tenofovir and emtricitabine (the drugs in Truvada) suppressed hepatitis B virus (HBV) replication more than tenofovir alone over 4 years for people with inactive or immune-tolerant disease, researchers reported at the EASL International Liver Congress (EASL 2013) this week in Amsterdam. The benefits of treatment at this early stage, however, remain uncertain.

Control Not Cure

Compared with the rapid developments in the hepatitis C field, treatment for chronic hepatitis has been stable in recent years. Nucleoside/nucleotide analogues including tenofovir (Viread) and entecavir (Baraclude) can maintain long-term viral suppression, but they seldom produce sustained virological response after stopping treatment, and rarely lead to hepatitis B surface antigen (HBsAg) loss or antibody seroconversion.

But the hepatitis B field may be "evolving toward a cure," Fabien Zoulim from Hospital Hôtel Dieu in Paris said at an EASL press conference on Thursday.

Unlike HIV, HBV does not require viral integration into the host cell genome in order to replicate, but integration can trigger liver cancer.

W. Ray Kim and colleagues reported that long-term HBV suppression using tenofovir significantly reduced the risk of developing hepatocellular carcinoma (HCC) over 6 years. Looking at data from the REVEAL-HBV trial, Jessica Liu and colleagues found that serum HBV DNA clearance significantly lowered the risk of HCC, even if hepatitis B "e" antigen (HBeAg) and HBsAg clearance did not occur; conversely, HCC risk remained elevated in people who achieved HBeAg antigen clearance if viral load remained high.

Several researchers at EASL presented preliminary data on potential approaches -- some of them similar to ongoing HIV cure research -- for silencing, destroying, or eradicating free-floating bits of viral genetic material known as covalent closed circular or cccDNA. Some evidence indicates residual cccDNA increases HCC risk even when blood viral load is undetectable using standard assays.

One study found that small molecules targeting histone acetylation or methylation can suppress HBV transcription and replication. In another, antibodies that target the lymphotoxin beta receptor resulted in degradation of cccDNA in HBV-infected cells. Finally, inducing proliferation of human liver cells in a mouse model led to rapid reduction, though not elimination, of HBV cccDNA. More research is needed to determine if reducing or eliminating cccDNA can lower liver cancer risk.
Early Treatment

Researchers are also looking at earlier treatment of chronic hepatitis B. Current guidelines recommend treatment for people with active liver disease progression, indicated by elevated alanine or aspartate transaminase (ALT or AST) levels. Much HBV-related liver damage is not caused by the virus itself, but rather by the body's immune response. Elevated transaminases reflect liver inflammation, which over time promotes fibrosis as the liver attempts to repair itself.

Typically people with normal ALT levels -- known as immune-tolerant hepatitis B -- are not consideration candidates for treatment. But now that highly effective and well-tolerated therapies are available, some experts propose that treatment during this early stage could lower the risk of HCC and reduce HBV transmission, as people with immune-tolerant infection may have high viral loads.

Edward Gane from Auckland General Hospital presented findings from a study comparing tenofovir monotherapy -- the current standard of care for active chronic hepatitis B -- versus combination therapy using tenofovir plus emtricitabine (marketed as the Truvada coformulation for HIV treatment).

The study enrolled 126 chronic hepatitis B patients with high HBV viral load but ALT below the upper limit of normal. They were evenly divided between men and women, about 90% were Asian, and the average age was 33 years. Though pre-treatment biopsies were not done, they were not known to have cirrhosis. At baseline the mean HBV DNA level was 9.2 log IU/mL; about half had HBV genotype B and about 40% had genotype C.

Participants were randomly assigned to receive 300 mg tenofovir once-daily, either with or without 200 mg emtricitabine once-daily, for 192 weeks.

Results

    Viral load declined dramatically in both arms soon after starting treatment.
    By week 192, significantly more people achieved undetectable HBV DNA (< 69 IU/mL) in the combination arm compared with the tenofovir monotherapy arm, 76% vs 55%, respectively.
    About half the patients stopped treatment after 192 weeks, however, and their viral load returned to baseline levels.
    Serological response rates were very low both arms.
    6 tenofovir monotherapy recipients and 2 receiving the combination experienced HBeAg loss, and 5 and 0, respectively, had HBeAg seroconversion, but the differences did not reach statistical significance.
    No patients in either arm experienced HBsAg loss or seroconversion.
    In a univariate analysis, female sex, lower baseline HBsAg and HBV DNA levels, and use of combination therapy were associated with a greater likelihood of viral suppression.
    In a multivariate analysis, female sex (odds ratio 6.0) and combination therapy (odds ratio 3.9) remained the only significant predictors.
    Treatment was generally safe and well-tolerated.
    6 people receiving tenofovir alone and 3 taking the combination regimen experienced adverse events, which generally were not considered related to study drugs.
    No participants saw elevated creatinine levels or reduced creatinine clearance suggestive of kidney function impairment (a known tenofovir side effect).
    No tenofovir resistance mutations were detected through 192 weeks.

"Prolonged antiviral therapy maintains potent viral suppression and is safe in immunotolerant patients," the researchers concluded. "The underlying impaired immune responses to HBV in this population may explain the poor serological response rates to antiviral therapy."

The treatment advantage for women in this study was stronger than the effect usually seen in trials of active chronic hepatitis, leading the investigators to suggest that, "Gender may be an effect modifier in treating chronic HBV patients with high viral loads and normal ALT values."

Session chair Mark Thursz asked whether these findings suggest that treatment guidelines should be revised to recommend treatment for immune-tolerant patients.

Gane replied that while the study shows that we certainly can treat such individuals, the question is who will benefit. "We need to show that long-term viral suppression in patients with normal ALT will prevent progression and HCC," he said.

He noted that many patients in this situation are young women of childbearing potential, who are advised not to take tenofovir during early pregnancy due to its association with birth defects. An audience member further noted that young patients have a very low risk of liver cancer even without treatment.

"We'd like to know if there's a subset of patients with high risk of progression -- such as family history of liver cancer -- who may benefit from early treatment," Gane concluded.

4/29/13

References

HL Chan, AJ Hui, S Chan, E Gane, et al. Tenofovir DF (TDF) compared to emtricitabine (FTC)/TDF in HBeAg-positive, chronic hepatitis B (CHB) virus-infected patients in the immune tolerant (IT) phase. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 101.

WR Kim, T Berg, R Loomba, et al. Long term tenofovir disoproxil fumarate (TDF) therapy and the risk of hepatocellular carcinoma. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 43.

J Liu, HI Yang, MH Lee, et al. Seroclearance of HBV DNA predicts significantly reduced risk of hepatocellular carcinoma among those with high viral loads: a time-dependent analysis of serially measured biomarkers. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 40.

GA Palumbo, L Belloni, S Valente, et al. Suppression of hepatitis B virus (HBV) transcription and replication by small molecules that target the epigenetic control of nuclear cccDNA minichromosome. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 56.

J Lucifora, F Reisinger, Y Xia, et al. Lymphotoxin beta receptor activation leads to degradation of HBV cccDNA from infected hepatocytes. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 59.

L Allweiss, T Volz, K Giersch, et al. Proliferation of hepatitis B virus infected human hepatocytes  induces suppression of viral replication and rapid cccDNA decrease in humanized mice. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 127.

StephenW

替诺福韦和恩曲他滨（的药物Truvada的），抑制B型肝炎病毒（HBV）复制比独自无效或免疫耐受的疾病的人超过4年替诺福韦的组合，研究人员在EASL国际肝病大会（2013年EASL）本周在阿姆斯特丹。在这个早期阶段治疗的好处，但是，仍然不明朗。

控制不能治愈

慢性肝炎的治疗丙型肝炎领域的迅速发展相比，近年来一直稳定。核苷/核苷酸类似物，包括替诺福韦（Viread的）和恩替卡韦（博路定）可以保持长期抑制病毒，但他们很少在停止治疗后产生持续病毒学应答，很少导致乙肝表面抗原（HBsAg）损失或抗体血清学转换。

但乙肝领域可能会“演变往治疗”的Fabien Zoulim医院Dieu酒店在巴黎的欧洲肝脏研究学会（EASL）上周四的新闻发布会上说。

不同于HIV，HBV并不需要病毒整合到宿主细胞基因组中，以复制，但集成可以触发肝癌。

W.雷Kim和他的同事报告说，长期抑制HBV使用替诺福韦超过6年的发展肝细胞癌（HCC）的风险显着降低。寻找数据揭示乙肝病毒试验，杰西卡刘和他的同事们发现，血清HBV DNA间隙显着降低肝癌的风险，即使乙肝“e”的抗原（HBeAg）和乙肝表面抗原清除并没有出现，相反，肝癌的风险仍然升高的人谁获得HBeAg抗原的清除，如果病毒载量仍然很高。

一些研究人员在EASL提出了初步数据，对潜在的方法 - 他们中的一些类似到正在进行的治愈艾滋病研究 - 沉默，销毁或消除病毒遗传物质被称为共价闭合环状或cccDNA的自由浮动位。一些证据表明剩余的cccDNA的增加肝癌风险，即使当血液中病毒载量检测不到使用标准检测。

一项研究发现，小分子靶向组蛋白乙酰化或甲基化可以抑制乙肝病毒的转录和复制。在另一个，抗体为目标的淋巴毒素β受体降解的cccDNA，HBV感染的细胞。最后，诱导人的肝细胞的增殖，在小鼠模型中，导致迅速减少，但不消除，HBV cccDNA的。需要更多的研究，以确定是否减少或消除的cccDNA可以降低肝癌风险。
早期治疗

研究人员还在寻找早期治疗慢性乙型肝炎目前的指导方针建议治疗患有活动性肝病的进展，表示高架丙氨酸或天门冬氨酸转氨酶（ALT或AST）水平。大部分HBV相关的肝损害不是由病毒本身引起的，而是由机体的免疫反应。转氨酶升高反映肝脏的炎症，随着时间的推移促进肝脏纤维化尝试修复自己。

通常，ALT水平正常的人 - 被称为免疫耐受乙肝 - 不考虑治疗的候选人。但现在，高效，耐受性良好的治疗，一些专家建议，在这个早期阶段治疗可以降低肝癌的风险降低HBV母婴传播，感染免疫耐受的人可能有高病毒载量。

爱德华·甘恩从奥克兰总医院提出从比较研究的替诺福韦单药治疗的结果 - 现行标准的护理慢性活动性乙型肝炎 - 与使用替诺福韦+恩曲他滨（艾滋病毒治疗的Truvada的coformulation的销售）的联合治疗。

该研究纳入126例慢性乙型肝炎患者的HBV病毒载量高，但ALT正常上限以下。他们平分秋色男人和女人之间，约90％是亚裔，平均年龄为33岁。虽然治疗前活检不这样做，他们不知道自己有肝硬化。在基线HBV DNA水平平均为9.2日志IU /毫升，约半数HBV基因型B和C基因型约40％

参与者被随机分配接受替诺福韦300毫克，每日一次，带或不带恩曲他滨200毫克，每日一次，192个星期。

结果

    双臂很快开始治疗后病毒载量急剧下降。
    192周，HBV DNA检测不到（<69 IU / mL）的显着更多的人在替诺福韦单药治疗组，76％和55％，分别比组合臂。
    大约一半的患者停止治疗后192周，但是，和它们的病毒载量恢复到基线水平。
    血清学应答率非常低，这两种武器。
    6替诺福韦单药治疗者和2个接收组合经历HBeAg转阴，5和0，分别，HBeAg血清学转换，但差异并未达到统计上的意义。
    无论是手臂没有患者出现HBsAg消失或血清学转换。
    在单因素分析，女性，较低的基线HBsAg和HBV DNA水平，并使用联合治疗伴有抑制病毒的可能性更大。
    在多变量分析中，女性（比值比6.0）和联合治疗（比值比3.9）仍然是唯一显着的预测。
    治疗一般是安全和耐受性良好。
    6人单独接受替诺福韦和3的组合方案经历，一般不被认为研究药物相关的不良事件。
    没有与会者认为，肌酐水平升高，肌酐清除率降低，提示肾功能受损（替诺福韦副作用）。
    没有替诺福韦耐药突变检测通过192周。

“长期抗病毒治疗维持强效抑制病毒和免疫耐受患者是安全的，”研究人员得出结论。 “基础受损的免疫反应，在这一人群中HBV可以解释穷人的血清学应答率抗病毒治疗。”

在这项研究中的妇女的治疗优势强的效果比通常所见的试验，慢性活动性肝炎，导致调查表明，性别可能是在治疗慢性乙肝患者的病毒载量高和正常的ALT值效应调节。 “

会议主席马克Thursz询问这些研究结果表明，治疗指引免疫耐受的患者治疗建议，应修订。

甘恩回答说，虽然研究表明，我们当然可以治疗此类个人的问题是，谁将会受益。 “我们需要表明，长期抑制病毒防止进展和肝癌患者ALT正常，”他说。

他指出，在这种情况下，许多患者是年轻女性的生育能力，不宜服用替诺福韦在妊娠早期，由于其与出生缺陷。观众成员进一步指出，年轻患者有肝癌的风险非常低，即使没有治疗。

“我们想知道，如果有进展的高风险 - 如家族史的肝癌 - 谁可能受益于早期治疗的患者的一个子集，”甘恩的结论。

13年4月29日

参考文献

HL，AJ辉陈甘恩，E，S，陈等人。替诺福韦（TDF），恩曲他滨（FTC）/ TDF HBeAg阳性慢性乙型肝炎（CHB）病毒感染者的免疫耐受（IT）相。肝脏研究欧洲协会第48届年会（EASL 2013）。阿姆斯特丹。 2013年4月24-28日。摘要101。

WR金，T伯格，R Loomba，等。长期替诺福韦酯富马酸（TDF）治疗和肝癌的风险。肝脏研究欧洲协会第48届年会（EASL 2013）。阿姆斯特丹。 2013年4月24-28日。摘要43。

J刘，杨喜，MH李，等。 HBV-DNA转阴预测肝癌的风险是那些具有高病毒载量明显减少：一个随时间变化的分析，连续监测的生物标志物。肝脏研究欧洲协会第48届年会（EASL 2013）。阿姆斯特丹。 2013年4月24-28日。摘要40。

GA帕隆博，L贝罗尼，S瓦伦特，等。抑制B型肝炎病毒（HBV）的转录和复制的小分子针对后生的cccDNA的核微小染色体控制。肝脏研究欧洲协会第48届年会（EASL 2013）。阿姆斯特丹。 2013年4月24-28日。摘要56。

F赖辛格，J Lucifora，Y夏，等。淋巴毒素β受体活化导致从受感染的肝细胞中HBV cccDNA的降解。肝脏研究欧洲协会第48届年会（EASL 2013）。阿姆斯特丹。 2013年4月24-28日。摘要59。

L Allweiss，T VOLZ，K吉尔施，等。 B型肝炎病毒感染的人类肝细胞增殖，诱导抑制病毒的复制和快速的cccDNA在人性化的小鼠减少。肝脏研究欧洲协会第48届年会（EASL 2013）。阿姆斯特丹。 4月24-28日，2013年。摘要127。

tonychant

HIV复方治疗药物有望治疗乙肝

一研究者声称，一种广泛用于艾滋病治疗的复方药物能够抑制肝炎患者体内乙肝病毒生长，即便是机体对该病毒产生耐受。

据新西兰奥克兰市立医院Edward Gane博士报道，在服用替诺福韦和恩曲他滨四年后，76%的患者体内乙肝病毒被抑制，没有耐受现象且安全性良好。

单独服用替诺福韦时乙肝病毒抑制率为55%，这显然比单独用药疗效更好（P=0.016），Gane在欧洲肝病研究协和的会议上报道说。

但是令人失望的是，很少有患者成功使免疫系统复原以应对病毒，并且在那些试验后停止治疗的患者中检测到他们的病毒载量反弹回早期水平，Gane说。

处于所谓的乙肝病毒免疫耐受阶段的乙肝患者病毒载量很高，并且没有明显的免疫反应；尽管前期的研究表明替诺福韦能够抑制乙肝病毒，但现行的用药指南并没有推荐该治疗方案。

Gane说现在仍然不清楚这些用药指南是否应该被他的发现所取代，并迫切希望进行长疗程的前瞻性研究以观察病毒载量的抑制能否减少例如肝硬化和肝癌等并发症。

研究者们招募了126名乙肝患者，这些肝炎患者血浆病毒载量达到至少1.7 x 107 IU / mL，并且血清谷丙转氨酶水平正常。

他们每天被随机的发放给替诺福韦和一种安慰剂或者替诺福韦和恩曲他滨。

研究的主要终点是患者病毒载量达到少于69 IU/ mL的比例，次级终点包括乙肝病毒E抗原消失和针对相应抗原的抗体的产生（HBeAg血清学转变）。

达到主要终点的实际肝炎患者人数分别是 ----- 服用替诺福韦组里64人中有35人达到该标准，联合用药组里62人中有47人达到该标准，甚至在那些有持续性病毒血症患者中也没有出现耐受性转变，Gane报道说。

但是仅有5名参与者出现乙肝病毒E抗原消失，3名参与者出现血清学转变。而且，没有患者出现病毒表明抗原消失（HBsAg是一种感染乙肝病毒的迹象），也没有患者产生针对该抗原的抗体。

大约一半的肝炎患者在研究结束后停止了治疗，并且在所有的这些患者中检测到他们的病毒载量在24周内反弹到研究前的水平。

该研究非常重要，法国里昂Hôtel Dieu医院的Fabien Zoulim博士评论说道，尽管他没有参与该项研究。Zoulim主持了这次欧洲肝病研究协会的记者会。

“但是它还处于第一阶段”，他告诉《今日医学头条》说，“我们已经表明我们能抑制该病毒，下一步就是我们能否阻止一些疾病的进展。”

他解释说道，用药指南在治疗一些选择性免疫耐受患者，如有肝硬化和肝癌家族史患者时，提供开放性的治疗选择。“我们现在有了更多的数据，所以我们在处理这类患者时将会变得更加自信”，他说道。

咬牙硬挺

孕期早期不能服用替诺吗？